U.S. patent number 10,675,602 [Application Number 16/405,777] was granted by the patent office on 2020-06-09 for spray-drying process.
This patent grant is currently assigned to Bend Research, Inc.. The grantee listed for this patent is Bend Research, Inc.. Invention is credited to John M. Baumann, Devon B. DuBose, Dwayne T. Friesen, Douglas L. Millard, David D. Newbold.
United States Patent |
10,675,602 |
Friesen , et al. |
June 9, 2020 |
Spray-drying process
Abstract
The process comprises delivering a spray solution comprising an
active agent and a matrix material in an organic solvent to a
spray-drying apparatus, atomizing the spray solution into droplets
within the spray-drying apparatus to remove at least a portion of
the organic solvent from the droplets to form a plurality of
particles, and collecting the particles. The spray solution may be
formed by forming a feed suspension comprising the active agent,
the matrix material, and the organic solvent, wherein the feed
suspension is at a temperature T.sub.1, and directing the feed
suspension to a heat exchanger, thereby increasing the temperature
of the feed suspension to a temperature T.sub.2, wherein T.sub.2 is
greater than T.sub.1, and the spray solution is at a pressure
greater than the vapor pressure of the organic solvent at T.sub.2,
such that the active agent and matrix material are soluble in the
organic solvent at T.sub.2.
Inventors: |
Friesen; Dwayne T. (Bend,
OR), Newbold; David D. (Bend, OR), Baumann; John M.
(Bend, OR), DuBose; Devon B. (Bend, OR), Millard; Douglas
L. (Bend, OR) |
Applicant: |
Name |
City |
State |
Country |
Type |
Bend Research, Inc. |
Bend |
OR |
US |
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Assignee: |
Bend Research, Inc. (Bend,
OR)
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Family
ID: |
42320878 |
Appl.
No.: |
16/405,777 |
Filed: |
May 7, 2019 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20190262791 A1 |
Aug 29, 2019 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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15670757 |
Aug 7, 2017 |
10300443 |
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13259082 |
Aug 8, 2017 |
9724664 |
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PCT/US2010/027930 |
Mar 19, 2010 |
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61164353 |
Mar 27, 2009 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
B01J
2/04 (20130101) |
Current International
Class: |
B01J
2/02 (20060101); B01J 2/04 (20060101); B01J
2/16 (20060101); B01J 2/00 (20060101) |
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Primary Examiner: Chang; Kyung S
Attorney, Agent or Firm: Klarquist Sparkman, LLP
Parent Case Text
CROSS REFERENCE TO RELATED APPLICATIONS
This is a continuation of application Ser. No. 15/670,757, filed
Aug. 7, 2017, which is a continuation of application Ser. No.
13/259,082, filed Sep. 22, 2011, issued as U.S. Pat. No. 9,724,664,
which is the U.S. National Stage of International Application No.
PCT/US2010/027930, filed Mar. 19, 2010, which was published in
English under PCT Article 21(2), which in turn claims the benefit
of U.S. Provisional Application No. 61/164,353, filed Mar. 27,
2009, each of which is incorporated herein in its entirety by
reference.
Claims
What is claimed is:
1. A spray-drying process, comprising: (a) forming a feed
suspension in a tank at a temperature T.sub.1, the feed suspension
comprising an active agent, a matrix material, and an organic
solvent, wherein the active agent is suspended in the organic
solvent and the matrix material is dissolved in the organic
solvent, and wherein the organic solvent contains less than 25 wt %
water; (b) flowing the feed suspension from the tank through a
flow-through heat exchanger located downstream of and separate from
the tank and upstream of a spray drying apparatus, the flow-through
heat exchanger comprising a feed suspension inlet and a spray
solution outlet to form a spray solution, wherein the feed
suspension entering the feed suspension inlet is at the temperature
T.sub.1, wherein the temperature T.sub.1 is below the
ambient-pressure boiling point of the organic solvent and the
matrix material is dissolved in the organic solvent at the
temperature T.sub.1, and the spray solution at the spray solution
outlet is at a temperature T.sub.2 and at a pressure that is
greater than the vapor pressure of the organic solvent at the
temperature T.sub.2, such that the active agent and the matrix
material are soluble in the organic solvent at the temperature
T.sub.2, wherein T.sub.2>T.sub.1, (c) directing the spray
solution to the spray-drying apparatus via a nozzle positioned
proximate the spray solution outlet of the flow-through heat
exchanger, wherein the spray solution is delivered to the nozzle at
a temperature T.sub.3, wherein the temperature T.sub.3 is less than
or equal to the temperature T.sub.2; and (d) atomizing the spray
solution into droplets within the spray-drying apparatus through
the nozzle to remove at least a portion of the organic solvent from
the droplets to form a plurality of particles having an average
diameter ranging from 0.5 .mu.m to 500 .mu.m, wherein the particles
comprise a homogeneous solid amorphous dispersion of the active
agent and the matrix material, wherein the spray solution is at the
temperature T.sub.2 for less than 5 minutes.
2. The spray-drying process of claim 1, wherein the matrix material
comprises a polymer.
3. The spray-drying process of claim 1, wherein the matrix material
comprises polyvinylpyrrolidone, a vinyl acetate/vinylpyrrolidone
copolymer, a vinyl acetate/vinyl alcohol copolymer, hydroxyethyl
cellulose, hydroxypropyl methylcellulose, hydroxypropyl
methylcellulose phthalate, carboxymethyl cellulose, carboxymethyl
ethylcellulose, hydroxypropyl methylcellulose acetate succinate,
cellulose acetate phthalate, cellulose acetate trimellitate,
cellulose, starch, dextran, pullulan, dextrin, maltodextrin,
glycogen, inulin, fructan, mannan, chitin, polydextrose, fleximer,
cellulose acetate, ethyl cellulose, hydroxypropyl methyl cellulose,
hydroxyethyl cellulose, a polyacrylate, a polymethacrylate,
polyethylene, polyoxyethylene, polypropylene, a polyamide, a
polyester, a polycarbonate, or any combination thereof.
4. The spray-drying process of claim 1, wherein the matrix material
comprises hydroxypropyl methylcellulose acetate succinate,
hydroxypropyl methylcellulose, hydroxypropyl methylcellulose
phthalate, cellulose acetate phthalate, cellulose acetate
trimellitate, carboxymethyl ethylcellulose, dextran, or any
combination thereof.
5. The spray-drying process of claim 1, wherein the matrix material
comprises hydroxypropyl methylcellulose acetate succinate.
6. The spray-drying process of claim 5, wherein the organic solvent
comprises acetone and less than 25 wt % water.
7. The spray-drying process of claim 1, wherein the total
concentration of the active agent and the matrix material in the
organic solvent is within a range of from 0.5 wt % to 12 wt %.
8. The spray-drying process of claim 1, wherein the temperature
T.sub.2 is at least 10.degree. C. greater than the temperature
T.sub.1.
9. The spray-drying process of claim 1, wherein the temperature
T.sub.2 is at least 30.degree. C. greater than the temperature
T.sub.1.
10. The spray-drying process of claim 1, wherein the temperature
T.sub.2 is at least 50.degree. C. greater than the temperature
T.sub.1.
11. The spray-drying process of claim 1, wherein the temperature
T.sub.2 is at least 10.degree. C. greater than a temperature
T.sub.A, wherein the temperature T.sub.A is the temperature at
which the active agent solubility equals the active agent
concentration in the organic solvent.
12. The spray-drying process of claim 1, wherein the organic
solvent is acetone, methanol, ethanol, n-propanol, isopropanol,
butanol, methyl ethyl ketone, methyl isobutyl ketone, ethyl
acetate, propyl acetate, tetrahydrofuran, acetonitrile, methylene
chloride, toluene, 1,1,1-trichloroethane, or any mixture thereof,
and contains less than 25% water.
13. The spray-drying process of claim 1, wherein the spray solution
is at a temperature greater than T.sub.3 for less than 5
minutes.
14. The spray-drying process of claim 1, wherein the spray solution
is at a temperature greater than T.sub.3 for less than 1 minute.
Description
BACKGROUND
A novel spray-drying process is disclosed. The process can lead to
spray-dried products with improved properties, as well as increased
throughput relative to conventional spray-drying processes.
The use of spray drying to produce powders from fluid feed stocks
is well known, with applications ranging from powdered milk to bulk
chemicals and pharmaceuticals. See U.S. Pat. No. 4,187,617 and
Mujumbar et al., Drying 91, pages 56-73 (1991). See also Masters,
Spray Drying Handbook, pages 263-268 (4th edition, 1985). The use
of spray drying to form solid amorphous dispersions of drugs or
active agents and concentration-enhancing polymers is also known.
See commonly owned U.S. Pat. Nos. 6,763,607 and 6,973,741.
When it is desired to form a spray-dried product in which the drug
or active agent is amorphous, it is desirable to have the active
agent fully dissolved in the spray solution when it is atomized
into droplets. Specifically, when it is desired to form a
spray-dried product in which the amorphous active agent is
dispersed in one or more other materials, termed matrix material,
it is generally desired to have at least a part and often all of
the matrix material also dissolved in the spray solution. In such
cases, the throughput of a conventional spray-drying process is
often limited by the amount of active agent and matrix material
that can be dissolved in the spray solution. It is generally known
that the solubility of many substances, such as active agents and
matrix materials, often increases as the temperature of the solvent
is increased. However, industry avoids using elevated temperatures
when using organic solvents, due to the inherent dangers and safety
concerns when processing organic solvents, which are often
flammable at high temperatures. In addition, conventional
spray-drying processes avoid use of elevated temperatures out of
concern for the thermal stability of the active agent and matrix
material--degradation of the active agent and/or the matrix
material can lead to unwanted breakdown products in the particles
produced.
Because of this, conventional spray-drying solutions are generally
kept at or near room temperature when entering the spray nozzle.
This limits the throughput of the process due to the often low
solubility of active agents and matrix materials in the solvents
used. In addition, when the solubility of the active agent in the
spray solution is low, the active agent is often dissolved to near
its solubility limit to achieve as high a throughput as possible.
The spray-dried products obtained from such solutions are often not
homogeneous. Finally, conventional spray-dried processes often
produce products that suffer from not being homogeneous because the
rate of solvent removal is not sufficiently fast, and broad ranges
of particle sizes are produced because the atomization means
produces a wide range of droplet sizes.
U.S. Patent Application Publication No. 2008/0248114A1 describes
the production of solid solutions containing poorly-soluble active
substances using a spray-drying process utilizing short-term
heating and rapid drying. The process avoids organic solvents by
utilizing a feed stream that is an aqueous suspension of the
active. The aqueous suspension is heated to allow dissolution of
the active in the spray solution. However, this process is limited
to actives that have a high solubility in water at elevated
temperature.
What is needed is a spray-drying process that results in improved
properties of the spray-dried product, such as a higher degree of
homogeneity and more uniform particle size, and that improves the
throughput of spray-drying equipment while spraying solutions of an
active agent and the matrix material, and provides a safe,
reproducible process to produce high-quality product. Such a
process promises to increase the quality and decrease manufacturing
costs for spray-dried products.
SUMMARY
A process for increasing the throughput of a spray drier comprises
(a) delivering a spray solution comprising an active agent and a
matrix material in an organic solvent to a spray-drying apparatus,
(b) atomizing the spray solution into droplets within the
spray-drying apparatus to remove at least a portion of the organic
solvent from the droplets to form a plurality of particles, and (c)
collecting the particles. The spray solution is formed by forming a
feed suspension comprising the active agent, the matrix material,
and the organic solvent, wherein the feed suspension is at a
temperature T.sub.1, and directing the feed suspension to a heat
exchanger, thereby increasing the temperature of the feed
suspension to a temperature T.sub.2, wherein (i) temperature
T.sub.2 is greater than temperature T.sub.1, and (ii) the spray
solution is at a pressure that is greater than the vapor pressure
of the solvent at temperature T.sub.2, such that substantially all
of the active agent in the spray solution and at least a portion of
the matrix material are soluble in the solvent at temperature
T.sub.2.
In one embodiment, temperature T.sub.2 is greater than the
ambient-pressure boiling point of the organic solvent.
In another embodiment, the nozzle used for atomization of the spray
solution is a pressure nozzle. In another embodiment, the nozzle
used for atomization of the spray solution in the spray-drying
apparatus is a flash nozzle. A flash nozzle utilizes a pressure
drop that induces cavitation in the spray solution prior to exiting
the nozzle orifice to induce droplet formation. A sweep gas around
the orifice is used to eliminate or reduce solids build-up during
operation.
In another aspect, the matrix material comprises a polymer.
In still another aspect, the particles comprise a solid amorphous
dispersion of the active agent and a polymer.
The disclosed processes provide one or more advantages over a
conventional spray-drying process. Certain embodiments of the
disclosed processes can increase the throughput of a spray dryer by
forming a spray solution that has a higher concentration at a
higher temperature than conventional processes. Additionally,
certain embodiments of the disclosed processes allow spray-drying
solutions wherein ratio of the concentration of active agent in the
spray solution to the solubility of the active agent in the organic
solvent at the atomization temperature is significantly less than
one, preferably less than 0.5, and even more preferably less than
0.3. Operating in this regime generally leads to spray-dried
products that are more homogeneous and more uniform. In addition,
the disclosed processes result in rapid evaporation of the organic
solvent, and shorter times to solidification than conventional
processes. Furthermore, in some embodiments, the process results in
improved atomization of the spray solution relative to conventional
processes due to the temperature of the spray solution when it is
atomized being above the boiling point of the solvent at the
pressure of the drying chamber.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
FIG. 1 is a schematic of a spray-drying apparatus suitable for use
in performing the process of the invention.
FIG. 2 is a schematic of a flash nozzle, suitable for use in
performing the process of the invention.
FIG. 3 is a figure showing the results of powder X-ray diffraction
of the samples of Example 1, Control 1, and Control 2.
DETAILED DESCRIPTION
A spray-drying process for producing a composition comprising an
active agent and a matrix material is described. The spray-drying
process, suitable apparatus for carrying out the process, and
suitable active agents and matrix materials are described in detail
below.
Unless otherwise indicated, all numbers expressing quantities of
components, molecular weights, percentages, temperatures, times,
and so forth, as used in the specification or claims are to be
understood as being modified by the term "about." Accordingly,
unless otherwise indicated, implicitly or explicitly, the numerical
parameters set forth are approximations that may depend on the
desired properties sought and/or limits of detection under standard
test conditions/methods. When directly and explicitly
distinguishing embodiments from discussed prior art, the embodiment
numbers are not approximates unless the word "about" is
recited.
Spray-Drying Process
The term spray drying is used conventionally and broadly refers to
processes involving breaking up liquid mixtures into small droplets
(atomization) and rapidly removing solvent from the mixture in a
container (drying chamber) where there is a strong driving force
for evaporation of solvent from the droplets. The strong driving
force for solvent evaporation is generally provided by maintaining
the partial pressure of solvent in the spray-drying apparatus well
below the vapor pressure of the solvent at the temperature of the
drying droplets. This is accomplished by (1) mixing the liquid
droplets with a warm drying gas, (2) maintaining the pressure in
the spray-drying apparatus at a partial vacuum (e.g., 0.01 atm to
0.50 atm), or (3) both.
Generally, the temperature and flow rate of the drying gas is
chosen so that the droplets of spray solution are dry enough by the
time they reach the wall of the apparatus that they are essentially
solid, form a fine powder, and do not stick to the apparatus wall.
The actual length of time to achieve this level of dryness depends
on the size of the droplets and the conditions at which the process
is operated. Droplet sizes may range from 1 .mu.m to 500 .mu.m in
diameter, the size being dependent on the desired particle size of
the spray dried powder. The large surface-to-volume ratio of the
droplets and the large driving force for evaporation of solvent
lead to actual drying times of a few seconds or less, and often
less than 0.1 second. Solidification times should be less than 100
seconds, and often less than a few seconds.
Turning to the drawings, wherein the same numerals refer to like
elements, there is shown in FIG. 1 an apparatus 10 suitable for
performing embodiments of the disclosed processes. In the following
discussion it is assumed that the spray-drying apparatus is
cylindrical. However, the dryer may take any other cross-sectional
shape suitable for spray drying a spray solution, including square,
rectangular, and octagonal, among others. The spray-drying
apparatus is also depicted as having one nozzle. However, multiple
nozzles can be included in the spray-drying apparatus to achieve
higher throughput of the spray solution.
The apparatus shown in FIG. 1 includes a feed suspension tank 20, a
heat exchanger 30, a drying chamber 40, a nozzle 50, and a
particle-collection means 60. In one embodiment, the process is
performed as follows. An active agent and a matrix material are
combined with an organic solvent in the feed suspension tank 20 to
form a feed suspension. The feed suspension is at a temperature
T.sub.1, which is below the ambient-pressure boiling point of the
organic solvent. Temperature T.sub.1 is also below either T.sub.A,
the temperature at which the active agent solubility equals the
active agent concentration in the organic solvent, or T.sub.M, the
temperature at which the matrix material solubility equals the
matrix material concentration in the organic solvent. At least a
portion of the active agent, a portion of the matrix material, or a
portion of both the active agent and the matrix material are
suspended, that is not dissolved, in the organic solvent. An
optional mixing means 22 may be used to keep the feed suspension
homogeneous while processing. When the organic solvent is
flammable, oxygen is normally excluded from all parts of the drying
apparatus. In particular, an inert gas, such as nitrogen, helium,
argon, and the like, is often used to fill the void space in the
feed suspension tank for safety reasons.
As used herein, the term "feed suspension" means a composition
comprising an active agent, a matrix material, and an organic
solvent, wherein at least a portion of the active agent, a portion
of the matrix material, or a portion of both active agent and
matrix material are suspended or not dissolved in the organic
solvent. In one embodiment, the feed suspension consists
essentially of an active agent, a matrix material, and an organic
solvent. In still another embodiment, the feed suspension consists
of an active agent, a matrix material, and an organic solvent. In
yet another embodiment, the feed suspension consists of particles
of active agent suspended in a solution of matrix material
dissolved in the organic solvent. It will be recognized that in
such feed suspensions, a portion of the active agent and the matrix
material may dissolve up to their solubility limits at the
temperature of the feed suspension.
As used herein, the term "organic solvent" means an organic
compound that can be used to dissolve the active agent and the
matrix material at elevated temperature. In one embodiment, the
solvent is volatile, having an ambient-pressure boiling point of
150.degree. C. or less. In another embodiment, the solvent has an
ambient-pressure boiling point of 100.degree. C. or less. Suitable
solvents include alcohols such as methanol, ethanol, n-propanol,
isopropanol, and butanol; ketones such as acetone, methyl ethyl
ketone and methyl isobutyl ketone; esters such as ethyl acetate and
propyl acetate; and various other solvents, such as
tetrahydrofuran, acetonitrile, methylene chloride, toluene, and
1,1,1-trichloroethane. Lower volatility solvents such as
dimethylacetamide or dimethylsulfoxide can also be used, generally
in combination with a volatile solvent. Mixtures of solvents, such
as 50% methanol and 50% acetone, can also be used, as can mixtures
with water. In one embodiment, the organic solvent contains less
than 50 wt % water. In another embodiment, the organic solvent
contains less than 25 wt % water. In still another embodiment, the
organic solvent contains less than 10 wt % water. In yet another
embodiment, the organic solvent contains less than 5 wt % water. In
another embodiment, the organic solvent contains essentially no
water.
For convenience, the feed suspension is often maintained at
near-ambient temperatures; however, this is not a limitation of the
disclosed processes. Generally, the temperature of the feed
suspension, T.sub.1, can range from 0.degree. C. to 50.degree. C.
or even higher. Temperatures of less than 0.degree. C. may also be
utilized, especially when there are stability concerns about the
active agent.
The feed suspension in the feed suspension tank 20 is delivered to
a pump 24, which directs the feed suspension to a heat exchanger
30. The heat exchanger has a feed suspension inlet 26, a spray
solution outlet 36, a heating fluid inlet 32, and a heating fluid
outlet 34. In the heat exchanger 30, the feed suspension enters
through the feed suspension inlet 26 at temperature T.sub.1, and
exits as the spray solution through the spray solution outlet 36 at
temperature T.sub.2. Spray solution temperature T.sub.2 is greater
than feed suspension temperature T.sub.1. To prevent unwanted
vaporization/boiling of the organic solvent in the spray solution,
pump 24 increases the pressure of the spray solution such that the
pressure of the spray solution at spray solution outlet 36 is
greater than the vapor pressure of the organic solvent at
temperature T.sub.2. The temperature of the spray solution when it
enters the nozzle 50 is generally near T.sub.2. Preferably it is
within 30.degree. C. of temperature T.sub.2. In addition, T.sub.2
is greater than or equal to the lesser of T.sub.A and T.sub.M. In
one embodiment, T.sub.2 is greater than or equal to the greater of
T.sub.A and T.sub.M. When it is the object of the process to form a
solid amorphous dispersion of the active agent and the matrix
material, T.sub.2 is greater than or equal to T.sub.A. Preferably,
T.sub.2 is at least 10.degree. C. greater than T.sub.A. In one
embodiment, the spray solution temperature T.sub.2 is greater than
the ambient-pressure boiling point of the organic solvent.
The spray solution exiting the heat exchanger may be at any
temperature, T.sub.2, which is greater than T.sub.1, as long as
T.sub.2 is greater than or equal to the lesser of T.sub.A and
T.sub.M. Temperature T.sub.2 may be at least 10.degree. C. greater
than T.sub.1, at least 20.degree. C. greater than T.sub.1, at least
30.degree. C. greater than T.sub.1, at least 40.degree. C. greater
than T.sub.1, or even at least 50.degree. C. greater than T.sub.1.
In one embodiment, temperature T.sub.2 is at least 50.degree. C. In
another embodiment, temperature T.sub.2 is at least 70.degree. C.
In another embodiment, temperature T.sub.2 is at least 80.degree.
C. In another embodiment, temperature T.sub.2 is at least
90.degree. C. In another embodiment, T.sub.2 is at least
100.degree. C. In still another embodiment, T.sub.2 is at least
120.degree. C.
The active agent and the matrix material are both soluble in the
organic solvent at temperature T.sub.2. By "soluble" is meant that
essentially all of the active agent and matrix material are
dissolved in the organic solvent at temperature T.sub.2. In the
case of the active agent, the term "dissolved" has the conventional
meaning, indicating that the active agent has gone into solution.
In the case of matrix materials, the term "dissolved" can take a
broader definition. For some matrix materials, such as polymers,
the term dissolved can mean the polymer has gone into solution, or
it can mean the polymer is dispersed or highly swollen with the
organic solvent such that it acts as if it were in solution. In
contrast, at temperature T.sub.1, at least one of the active agent
and the matrix material are present as a suspension in the organic
solvent. Any suitable technique may be used to determine if the
active agent and matrix material are soluble in the organic solvent
at temperature T.sub.2. Examples include dynamic or static light
scattering analysis, turbidity analysis, and visual observations.
In one embodiment, the spray solution comprises the active agent
and the matrix material dissolved in the organic solvent at
temperature T.sub.2.
In one embodiment, temperature T.sub.2 is greater than the
temperature at which the active agent and matrix material are
soluble in the organic solvent. That is, T.sub.2 is greater than or
equal to the greater of T.sub.A and T.sub.M. It may be desirable
that temperature T.sub.2 be much greater than the greater of
T.sub.A and T.sub.M. Thus, temperature T.sub.2 may be at least
10.degree. C. greater than the greater of T.sub.A and T.sub.M, at
least 20.degree. C. greater than the greater of T.sub.A and
T.sub.M, or even at least 30.degree. C. greater than the greater of
T.sub.A and T.sub.M. Spray-dried products made by embodiments of
the disclosed processes are typically more uniform and homogeneous
when temperature T.sub.2 is greater than the greater of T.sub.A and
T.sub.M.
In one embodiment, the pump 24 increases the pressure of the spray
solution to a pressure ranging from 2 atm to 400 atm. In another
embodiment, the pressure of the spray solution as it exits the heat
exchanger 30 is greater than 10 atm.
The heat exchanger 30 may be of any design wherein heat is
transferred to the feed suspension resulting in an increase in
temperature. In one embodiment, the heat exchanger 30 is an
indirect heat exchanger, wherein a heating fluid is in contact with
the feed suspension through a heat-transfer surface. Exemplary
indirect heat exchangers include tube-in-tube devices and
tube-in-shell devices, both well-known in the art. The heat
exchanger 30 may also be a direct heat exchanger, in which a
heating fluid, such as steam, is injected directly into the feed
suspension, resulting in an increase in the temperature of the feed
suspension. In yet another embodiment, the feed suspension flows
over a hot surface, such as a resistance heating element, resulting
in an increase in temperature of the feed suspension. Other heating
sources may also be used, such as microwaves and ultrasonic devices
that can increase the temperature of the feed suspension.
The concentration of active agent and matrix material in the spray
solution can be virtually any value. In one embodiment, the
concentration of total solids (that is, active agent and matrix
material) in the organic solvent is at least 0.5 wt %. The
concentration of total solids in the organic solvent may be at
least 1 wt %, at least 5 wt %, or even at least 10 wt % or more. In
another embodiment, the concentration of active agent in the
organic solvent is at least 1.25-fold the solubility of the active
agent in the organic solvent at temperature T.sub.1. The
concentration of active agent in the organic solvent may be at
least 1.5-fold, at least 2.0-fold, or even 2.5-fold or more the
solubility of the active agent in the organic solvent at
temperature T.sub.1.
In one embodiment, the residence time of the feed suspension in the
heat exchanger 30 is minimized so as to limit the time the
suspension/solution is exposed to elevated temperatures. The
residence time of the suspension/solution in the heat exchanger may
be less than 30 minutes, less than 20 minutes, less than 10
minutes, less than 5 minutes, or even less than 1 minute.
The spray solution at the spray solution outlet 36 is directed to a
drying chamber 40, where it enters a nozzle 50 for atomizing the
spray solution into droplets 44. The temperature of the spray
solution when it enters the nozzle 50 is the spray temperature,
designated as T.sub.3. When it is desired to keep the active agent
and matrix material dissolved in the spray solution, it is often
desirable for T.sub.3 to be at or near T.sub.2. However, there are
sometimes advantages to having T.sub.3 significantly less than
T.sub.2. For example, degradation of the active agent may be
reduced or atomization in certain nozzles may be more effective
when T.sub.3 is significantly less than T.sub.2. In some cases, it
is even desirable for T.sub.3 to be sufficiently low that the
active agent, the matrix material, or both the active agent and the
matrix material are not soluble in the solvent. In such cases, the
solution may be below the point at which the solutes are soluble
for a sufficiently short time such that all the solutes remain in
solution until the solution is atomized. Alternatively, the
solution may be below the point at which the solutes are soluble
for a sufficiently long time that one or more of the matrix
material or the active agent may precipitate or crystallize from
solution. In one embodiment, temperature T.sub.3 is less than
5.degree. C. less than T.sub.2. In another embodiment, temperature
T.sub.3 is less than 20.degree. C. less than T.sub.2. In another
embodiment, temperature T.sub.3 is less than 50.degree. C. less
than T.sub.2. In still another embodiment, both temperatures
T.sub.2 and T.sub.3 are greater than the greater of T.sub.A and
T.sub.M. In one embodiment, temperatures T.sub.2 and T.sub.3 are at
least 5.degree. C. greater than the greater of T.sub.A and T.sub.M.
In another embodiment, temperatures T.sub.2 and T.sub.3 are at
least 20.degree. C. greater than the greater of T.sub.A and
T.sub.M. In yet another embodiment, temperatures T.sub.2 and
T.sub.3 are at least 50.degree. C. greater than the greater of
T.sub.A and T.sub.M.
In one embodiment, the apparatus 10 is designed such that the time
the spray solution is at a temperature greater than T.sub.3 is
minimized. This may be accomplished by locating the spray solution
outlet 36 as close as possible to the nozzle 50. Alternatively, the
size of the tubing or fluid connections between the spray solution
outlet 36 and the nozzle 50 may be small, minimizing the volume of
spray solution and reducing the time the spray solution is at a
temperature greater than T.sub.3. The time the spray solution is at
a temperature greater than T.sub.3 may be less than 30 minutes,
less than 20 minutes, less than 10 minutes, less than 5 minutes, or
even less than 1 minute.
Virtually any nozzle can be used to atomize the spray solution into
droplets. The inventors have found that pressure nozzles are
effective in embodiments of the disclosed processes. In another
embodiment, a flash nozzle is used, as described below.
The drying chamber 40 also has a source of heated drying gas 42
which is combined with the droplets 44 in the drying chamber 40. In
the drying chamber 40, at least a portion of the solvent is removed
from the droplets to form a plurality of particles comprising the
active agent and the matrix material. Generally, it is desired that
the droplets are sufficiently dry by the time they come in contact
with the drying chamber surface that they do not stick or coat the
chamber surfaces.
The particles, along with the evaporated solvent and drying gas,
exit the drying chamber at outlet 46, and are directed to a
particle-collection means 60. Suitable particle-collection means
include cyclones, filters, electrostatic particle collectors, and
the like. In the particle-collection means 60, the evaporated
solvent and drying gas 62 are separated from the plurality of
particles 66, allowing for collection of the particles.
The particles may be of any desired size. In one embodiment, the
particles have an average diameter ranging from 0.5 .mu.m to 500
.mu.m. In another embodiment, the particles have a diameter ranging
from 0.5 .mu.m to 100 .mu.m. In another embodiment, the particles
have an average diameter of greater than 10 .mu.m. In still another
embodiment, the particles have an average diameter of greater than
20 .mu.m. In still another embodiment, the particles have an
average diameter of greater than 30 .mu.m. In yet another
embodiment, the particles have a mass median aerodynamic diameter
ranging from 0.5 .mu.m to 10 .mu.m. In still another embodiment,
the particles have a mass median aerodynamic diameter ranging from
1 .mu.m to 5 .mu.m.
In one embodiment, the concentration of solvent remaining in the
particles when they are collected (that is, the concentration of
residual solvent) is less than 10 wt % based on the total weight of
the particles. In another embodiment, the concentration of residual
solvent in the particles when they are collected is less than 5 wt
%. In yet another embodiment, the concentration of residual solvent
in the particles is less than 3 wt %. In another embodiment, a
drying process subsequent to the spray-drying process may be used
to remove residual solvent from the particles. Exemplary processes
include tray drying, fluid-bed drying, vacuum drying, and the
drying processes described in WO2006/079921 and WO2008/012617.
In one embodiment, nozzle 50 is a flash nozzle 50a. There is shown
in FIG. 2 a cross-sectional schematic of a flash nozzle 50a. Flash
nozzle 50a consists of a central tube 51 and an outer tube 53.
Central tube 51 is in fluid communication with the inflowing spray
solution 55, while outer tube 53 is in fluid communication with a
sweep gas 52. The flash nozzle 50a has an inlet end, represented by
A, and an outlet end, represented by B. The spray solution 55 from
the heat exchanger 30 (not shown in FIG. 2) enters central tube 51
at A. A sweep gas 52 enters outer tube 53 at A. As spray solution
55 travels through the central tube 51 from inlet A to outlet B,
the pressure decreases due to pressure drop. Between the inlet A
and outlet B, the pressure of the spray solution 55 decreases to a
value that is less than the vapor pressure of the solvent in the
spray solution, leading to the formation of vapor bubbles of the
solvent (a process known as cavitation). By the time the spray
solution 55 reaches outlet B of the central tube 51, it is a fluid
56 comprising droplets of spray solution and vapor-phase solvent.
In one embodiment, the central tube 51 is coated with a non-stick
coating. In another embodiment, the outer tube 53 is coated with a
non-stick coating. In still another embodiment, the central tube 51
and the outer tube 53 are coated with a non-stick coating.
Non-stick coatings include, for example, polytetrafluoroethylene
(PTFE) or other suitable non-stick coatings.
The sweep gas 52 exiting through the outer tube outlet 58 is in
fluid communication with the fluid 56 exiting through the central
tube 51. The sweep gas 52 decreases the likelihood that solid
material will form at the exit from the central tube 51 or the
outer tube 53.
Active Agents
The process of the present invention is used to form a composition
comprising an active agent. By "active agent" is meant a drug,
medicament, pharmaceutical, therapeutic agent, nutraceutical,
agrochemical, fertilizer, pesticide, herbicide, nutrient, or other
compound that may be desired to be formulated with a matrix
material. The active agent may be a "small molecule," generally
having a molecular weight of 2000 Daltons or less. The active agent
may also be a "biological active." Biological actives include
proteins, antibodies, antibody fragments, peptides,
oligoneucleotides, vaccines, and various derivatives of such
materials. In one embodiment, the active agent is a small molecule.
In another embodiment, the active agent is a biological active. In
still another embodiment, the active agent is a mixture of a small
molecule and a biological active. In yet another embodiment, the
compositions made by certain of the disclosed processes comprise
two or more active agents.
The active agent may be highly water soluble, sparingly water
soluble, or poorly water soluble. In one embodiment, the active
agent is "poorly water soluble," meaning that the active agent has
a solubility in water (over the pH range of 6.5 to 7.5 at
25.degree. C.) of less than 5 mg/mL. The active agent may have an
even lower aqueous solubility, such as less than about 1 mg/mL,
less than about 0.1 mg/mL, and even less than about 0.01 mg/mL.
Matrix Materials
The disclosed processes are used to form compositions comprising a
matrix material. Matrix materials suitable for use in the
compositions formed by the disclosed methods should be inert, in
the sense that they do not chemically react with the active agent
in an adverse manner. The matrix material can be neutral or
ionizable. In one embodiment, the composition includes two or more
matrix materials.
Exemplary matrix materials include polysaccharides. Polysaccharides
can be underivatized, such as cellulose, starch, dextran, pullulan,
dextrin, maltodextrin, glycogen, inulin, fructan, mannan, chitin,
polydextrose, fleximer (a ring-opened form of dextran), and
oligosaccharides. Often, derivatives and substituted versions of
the polysaccharides are preferred. Examples of such polysaccharide
derivatives include ester- and ether-linked derivatives. Included
in this class are cellulose ethers, cellulose esters, and cellulose
derivatives that have both ester and ether substituents. Specific
examples include cellulose acetate, ethyl cellulose, hydroxypropyl
methyl cellulose and hydroxyethyl cellulose. Starch derivatives
include starch acetate and carboxymethyl starch. Also included are
synthetic matrix materials, such as polyacrylates and
polymethacrylates, vinyl matrix materials, polyethylenes,
polyoxyethylenes, polypropylenes, polyamides, polyesters,
polycarbonates, and derivatives and substituted versions thereof;
copolymers of various types, including random and block copolymers;
other matrix materials such as lactose, trehalose, sucrose,
fructose, maltose, dextrose, xylitol, sorbitol, glycine, amino
acids, citric acid, phospholipids, bile salts; and mixtures
thereof.
In one embodiment, the matrix material is amphiphilic, meaning that
the matrix material has hydrophobic and hydrophilic portions. In
another embodiment, the matrix material is ionizable.
In yet another embodiment, the matrix material comprises a polymer.
Appropriate matrix polymers include polyvinylpyrrolidone, vinyl
acetate/vinylpyrrolidone copolymers, vinyl alcohol, vinyl
acetate/vinyl alcohol copolymers, hydroxyethyl cellulose,
hydroxypropyl methylcellulose, hydroxypropyl methylcellulose
phthalate, carboxymethyl cellulose, carboxymethyl ethylcellulose,
hydroxypropyl methylcellulose acetate succinate, cellulose acetate
phthalate and cellulose acetate trimellitate. In still another
embodiment, the matrix material comprises an ionizable cellulosic
polymer. In yet another embodiment, the matrix material comprises
an amphiphilic, ionizable polymer.
In one embodiment, the matrix material is biodegradable, meaning
that the matrix material will degrade over time. By "degrade" is
meant that in a use environment, the matrix material is broken down
into smaller species that can be absorbed, metabolized, or
otherwise eliminated or removed from the environment of use. This
degradation can occur through enzymatic, hydrolytic, oxidative, or
other reaction, as is well known in the art, or by degrading the
matrix material into aqueous soluble species that can readily be
removed from the environment of use.
Compositions
In one embodiment, the composition made by the disclosed processes
is in the form of a solid amorphous dispersion of the active agent
and the matrix material.
In another embodiment, the particles comprise a solid amorphous
dispersion of the active agent and matrix material consisting
essentially of amorphous active agent molecularly dispersed
throughout the matrix material. In this embodiment, the solid
dispersion may be considered a "solid solution" of active agent and
matrix material. The term "solid solution" includes both
thermodynamically stable solid solutions in which the active agent
is completely dissolved in the matrix material, as well as
homogeneous materials consisting of amorphous active agent
molecularly dispersed throughout the matrix material in amounts
greater than the solubility of the active agent in the matrix
material. A dispersion is considered a "solid solution" when it
displays a single glass-transition temperature when analyzed by
differential scanning calorimetry (DSC). In one embodiment, the
particles have at least one Tg due to the amorphous character of
the matrix material. In another embodiment, at least 90 wt % of the
active agent in the particles is amorphous. In yet another
embodiment, the active agent is amorphous and molecularly dispersed
in a portion of one or more of the matrix materials, while the
remaining portion of the matrix materials is present as a separate
phase. This separate phase matrix material may be amorphous,
crystalline, or a mixture of both amorphous and crystalline.
In another embodiment the particles comprise the active agent in
crystalline form, which is homogeneously or substantially
homogeneously distributed in the matrix material. In still another
embodiment, the particles comprise the active agent in amorphous or
non-crystalline form, which is homogeneously distributed in the
matrix material matrix. In yet another embodiment, the particles
comprise a mixture of active agent in crystalline and amorphous
forms homogeneously distributed in the matrix material.
In still another embodiment, the particles comprise a mixture of
active-agent-rich domains and matrix material-rich domains. The
active agent in the domains may be amorphous, crystalline, or a
mixture of amorphous and crystalline.
In yet another embodiment, the compositions comprise a third
component in addition to the active agent and the matrix material.
This third component may be any compound or mixture of compounds
that facilitates the intended use of the disclosed compositions.
Exemplary third components include, but are not limited to, matrix
materials, surface active agents, wetting agents, diluents,
fillers, bulking agents, disintegrants, flavors, fragrances,
buffering agents, and/or other components known in the art.
Without further elaboration, it is believed that one of ordinary
skill in the art can, using the foregoing description, utilize the
present invention to its fullest extent. Therefore, the following
specific embodiments are to be construed as merely illustrative and
not restrictive of the scope of the invention. Those of ordinary
skill in the art will understand that variations of the conditions
and processes of the following examples can be used.
EXAMPLES
Active Agent 1 was S-(fluoromethyl)
6.alpha.,9-difluoro-11.beta.,17-dihydroxy-16.alpha.-methyl-3-oxoandrosta--
1,4-diene-17.beta.-carbothioate, 17-propionate, also known as
fluticasone propionate, having the structure:
##STR00001## Active Agent 1 has a solubility of 0.4 .mu.g/mL in pH
7.4 buffer, and a Log P value of 3.7. The Tg of amorphous Active
Agent 1 was determined by DSC to be 84.degree. C. The room
temperature (20.degree. C. to 30.degree. C.) solubility of Active
Agent 1 in methanol is 0.3 wt %.
Example 1
A spray-dried dispersion was made using an apparatus similar to
that shown in FIG. 1. A feed suspension was prepared by mixing 3 gm
of Active Agent 1 and 9 gm of the MG grade of hydroxypropyl
methylcellulose acetate succinate (HPMCAS-MG, AQOAT-MG available
from Shin Etsu, Tokyo, Japan) with 88 gm of a methanol solvent. The
HPMCAS-MG dissolved in the solvent, while the active agent remained
in suspension. The feed suspension was maintained at ambient
temperature, 20.degree. C. to 30.degree. C., with stirring in a
pressure pot to prevent settling of the particles of Active Agent
1. The total solids content of the feed suspension was 12 wt %.
The feed suspension in the pressure pot was pressurized to 245 psig
and directed at a rate of 26 gm/min to a tube-in-shell heat
exchanger. Heating fluid at 160.degree. C. was circulated in a
countercurrent manner through the heat exchanger. The spray
solution exiting the heat exchanger was at a temperature, T.sub.2,
of 120.degree. C., and all of the active agent and matrix material
were dissolved in the spray solution. The average residence time of
the spray solution in the heat exchanger was less than 60 seconds.
The total time the spray solution was at a temperature of
120.degree. C. was less than 80 seconds. Thus, the elapsed time
from the time the spray solution exited the heat exchanger to the
time it exited the pressure nozzle was 20 seconds. The temperature
of the nozzle was 120.degree. C.
The spray solution was delivered to the spray-drying chamber where
it was atomized using a Schlick 2.0 pressure nozzle (Dusen-Schlick
GmbH of Untersiemau, Germany). The spray solution was atomized into
droplets within the spray-drying chamber, while simultaneously
mixing the droplets with a nitrogen drying gas which was introduced
to the drying chamber at a temperature of 140.degree. C. and at a
flow rate of 520 gm/min, resulting in the formation of solid
particles.
The solid particles, along with the evaporated solvent and the
drying gas, were directed to a cyclone separator, where the solid
particles were collected. The particles were subsequently dried in
a vacuum chamber at 0.15 atm for 2 to 3 hours to remove residual
methanol from the particles.
The resulting particles had 25 wt % Active Agent 1 in
HPMCAS-MG.
Control 1
As a control, a 25 wt % Active Agent 1 in HPMCAS-MG composition was
made using a conventional ambient-temperature spray-drying process.
For Control 1, a feed solution was formed by dissolving 0.45 gm of
Active Agent 1 and 1.35 gm of HPMCAS-MG in 179.7 gm methanol. Both
the active agent and the matrix material completely dissolved in
the methanol at ambient temperature. The total solids content of
this solution was 1.0 wt %.
This solution was spray dried using the same apparatus as described
for Example 1, except that the heat exchanger was bypassed, such
that the spray solution was not heated prior to atomization. All
other operating variables were nominally the same as described in
Example 1.
Control 2
As a second control, a feed suspension similar to that formed for
Example 1 was prepared and then spray dried without heating the
spray solution. The feed suspension consisted of 2.25 gm of Active
Agent 1, 6.75 gm of HPMCAS-MG, and 66 gm of methanol, resulting in
a feed suspension containing 12 wt % solids. Because the feed was a
suspension rather than a solution, a two-fluid nozzle was used
(manufactured by Spray Systems, Wheaton, Ill.) to avoid
clogging.
The feed suspension was spray dried using the same apparatus as
described for Example 1, except that the heat exchanger was
bypassed, such that the spray solution was not heated prior to
atomization, and a two-fluid nozzle was used for atomization of the
feed. All other operating variables were nominally the same as
described in Example 1.
Analysis of Compositions from Examples 1, Control 1, and Control
2
Samples of the compositions of Example 1, Control 1, and Control 2
were analyzed by powder X-ray diffraction using an AXS D8 Advance
PXRD measuring device (Bruker, Inc. of Madison, Wis.). Samples
(approximately 100 mg) were packed in Lucite sample cups fitted
with Si(511) plates as the bottom of the cup to give no background
signal. Samples were spun in the .phi. plane at a rate of 30 rpm to
minimize crystal orientation effects. The x-ray source
(KCu.sub..alpha., .lamda.=1.54 .ANG.) was operated at a voltage of
45 kV and a current of 40 mA. Data for each sample were collected
over a period of 27 minutes in continuous detector scan mode at a
scan speed of 1.8 seconds/step and a step size of
0.04.degree./step. Diffractograms were collected over the 2.theta.
range of 4.degree. to 40.degree..
FIG. 3 shows the results of this analysis. The composition of
Example 1, made using a concentrated feed suspension and a heat
exchanger to increase the feed temperature according to the
disclosed processes, showed an amorphous halo, indicating the
active agent in the composition was amorphous. Likewise, the
composition of Control 1, made using a conventional spray-drying
process using a dilute spray solution of active agent and matrix
material dissolved in a solvent at ambient temperature, also showed
only an amorphous halo. However, the composition of Control 2, made
using a concentrated feed suspension but not heated, showed a large
number of well-defined peaks, indicating the presence of
crystalline active agent in the composition.
This analysis shows that the compositions of Example 1 and Control
1 had similar properties. However, because the spray solution for
Example 1 contained 12 wt % solids, while the spray solution for
Control 1 only contained 1 wt % solids, certain embodiments of the
disclosed processes (Example 1) had a throughput that was 12-fold
greater than that of the conventional spray-drying process.
Example 2
A spray-dried dispersion is made using an apparatus similar to that
shown in FIG. 1 using the procedures outlined in Example 1, except
that the flash nozzle of FIG. 2 is used. The resulting particles
consist of 25 wt % Active Agent 1 in HPMCAS.
An embodiment of the disclosed spray-drying processes comprises
delivering a spray solution comprising an active agent and a matrix
material in an organic solvent to a spray-drying apparatus,
atomizing said spray solution into droplets within said
spray-drying apparatus via a nozzle to remove at least a portion of
the organic solvent from said droplets to form a plurality of
particles, wherein said spray solution is delivered to said nozzle
at a temperature T.sub.3, and collecting said particles, wherein
said particles comprise said active agent and said matrix material,
and wherein said spray solution is formed by forming a feed
suspension comprising said active agent, said matrix material and
said organic solvent, wherein said feed suspension is at a
temperature T.sub.1, and directing said feed suspension to a heat
exchanger, thereby increasing the temperature of said feed
suspension to a temperature T.sub.2, wherein temperature T.sub.2 is
greater than temperature T.sub.1, and said spray solution is at a
pressure that is greater than the vapor pressure of said solvent at
temperature T.sub.2, such that said active agent and said matrix
material are soluble in said solvent at temperature T.sub.2. In one
embodiment, said temperature T.sub.2 is greater than the
ambient-pressure boiling point of said solvent.
In either of the above embodiments, said active agent and said
matrix material may be soluble in said solvent at temperature
T.sub.3. In any or all of the above embodiments, said spray
solution may be atomized using a flash nozzle.
In any or all of the above embodiments, said temperature T.sub.2
may be at least 100.degree. C. In any or all of the above
embodiments, said spray solution may be at temperature T.sub.2 for
less than 10 minutes. Alternatively, said spray solution may be at
temperature T.sub.2 for less than 5 minutes.
In any or all of the above embodiments, said organic solvent is
selected from methanol, ethanol, n-propanol, isopropanol, butanol
acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl
acetate, propyl acetate, tetrahydrofuran, acetonitrile, methylene
chloride, toluene, 1,1,1-trichloroethane, and mixtures thereof. In
certain embodiments, said organic solvent is selected from the
group consisting of methanol, ethanol, n-propanol, isopropanol,
butanol acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl
acetate, propyl acetate, tetrahydrofuran, acetonitrile, methylene
chloride, toluene, 1,1,1-trichloroethane, and mixtures thereof. In
any or all of the above embodiments, said organic solvent may
contain less than 50 wt % water.
In any or all of the above embodiments, said particles may have a
mass median aerodynamic diameter ranging from 0.5 .mu.m to 10
.mu.m. In any or all of the above embodiments, said particles may
have an average diameter of greater than 10 .mu.m.
In any or all of the above embodiments, said matrix material may
comprise a polymer. In some embodiments, said particles comprise a
solid amorphous dispersion of said active agent in said
polymer.
Also disclosed are embodiments of products made by any or all of
the above processes. In some embodiments, the product comprises a
solid amorphous dispersion of said active agent and said
polymer.
An embodiment of a process for producing a composition comprises
forming a feed suspension comprising an active agent, a matrix
material and an organic solvent, wherein said feed suspension is at
a temperature T.sub.1, forming a spray solution by directing said
feed suspension to a heat exchanger, thereby increasing the
temperature of said feed suspension to a temperature T.sub.2,
wherein temperature T.sub.2 is greater than temperature T.sub.1,
said spray solution is at a pressure that is greater than the vapor
pressure of said solvent at temperature T.sub.2, and said active
agent and said matrix material are soluble in said solvent at
temperature T.sub.2, directing said spray solution to a
spray-drying apparatus, said spray-drying apparatus comprising a
drying chamber, a nozzle for atomizing said spray solution into
droplets, and a source of heated drying gas for removing at least a
portion of said organic solvent from said droplets, atomizing said
spray solution into droplets in said drying chamber by said nozzle,
wherein the spray solution is delivered to said nozzle at a
temperature T.sub.3, contacting said droplets with said heated
drying gas to remove at least a portion of said organic solvent
from said droplets to form a plurality of particles comprising said
active agent and said matrix material, and collecting said
particles. In some embodiments, said temperature T.sub.2 is greater
than the ambient-pressure boiling point of said solvent.
In either of the above embodiments, said active agent and said
matrix material may be soluble in said solvent at temperature
T.sub.3. Alternatively, said active agent or said matrix material
may not be soluble in said solvent at temperature T.sub.3.
The terms and expressions which have been employed in the foregoing
specification are used therein as terms of description and not of
limitation, and there is no intention in the use of such terms and
expressions of excluding equivalents of the features shown and
described or portions thereof, it being recognized that the scope
of the invention is defined and limited only by the claims which
follow.
* * * * *
References